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Laquinimod ameliorates secondary brain inflammation
Julia Nedelcu1, Christin Reinbach1, Philipp Riedler1
1Institute of Anatomy, Rostock University Medical Center, Rostock 18057, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich 80336, Germany.
Abstract:
Accumulating evidence suggests that a degenerative processes within the brain can trigger the formation of new, focal inflammatory lesions in Multiple Sclerosis (MS). Here, we used a novel pre-clinical MS animal model to test whether the amelioration of degenerative brain events reduces the secondary recruitment of peripheral immune cells and, in consequence, inflammatory lesion development. Neural degeneration was induced by a 3 weeks cuprizone intoxication period. To mitigate the cuprizone-induced pathology, animals were treated with Laquinimod (25 mg/kg) during the cuprizone-intoxication period. At the beginning of week 6, encephalitogenic T cell development in peripheral lymphoid organs was induced by the immunization with myelin oligodendrocyte glycoprotein 35-55 peptide (i.e., Cup/EAE). Demyelination, axonal injury and reactive gliosis were determined by immunohistochemistry. Positron emission tomography (PET) imaging was performed to analyze glia activation in vivo. Vehicle-treated cuprizone mice displayed extensive callosal demyelination, glia activation and enhanced TSPO-ligand binding. This cuprizone-induced pathology was profoundly ameliorated in mice treated with Laquinimod. In vehicle-treated Cup/EAE mice, the cuprizone-induced pathology triggered massive peripheral immune cell recruitment into the forebrain, evidenced by multifocal perivascular inflammation, glia activation and neuro-axonal injury. While anti myelin oligodendrocyte glycoprotein 35-55 peptide immune responses were comparable in vehicle- and Laquinimod-treated Cup/EAE mice, the cuprizone-triggered immune cell recruitment was ameliorated by the Laquinimod treatment. This study clearly illustrates that amelioration of a primary brain-intrinsic degenerative process secondary halts peripheral immune cell recruitment and, in consequence, inflammatory lesion development. These findings have important consequences for the interpretation of the results of clinical studies.
Insights
Degenerative brain processes in Multiple Sclerosis (MS) can cause inflammation. Ameliorating brain degeneration with Laquinimod reduced immune cell recruitment and inflammatory lesion development in a pre-clinical MS model.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Demyelinating diseases
Background:
- Brain degeneration can initiate inflammatory lesions in Multiple Sclerosis (MS).
- Understanding the link between primary neurodegeneration and secondary inflammation is crucial for MS treatment.
- Novel therapeutic strategies aim to halt disease progression by targeting early degenerative events.
Purpose of the Study:
- To investigate if mitigating primary neural degeneration reduces secondary peripheral immune cell infiltration and inflammatory lesion formation in a pre-clinical MS model.
- To evaluate the efficacy of Laquinimod in preventing cuprizone-induced neurodegeneration and subsequent inflammatory responses.
- To assess the impact of targeting neurodegeneration on immune cell recruitment in an experimental autoimmune encephalomyelitis (EAE) model.
Main Methods:
- Utilized a pre-clinical MS model involving cuprizone intoxication to induce neural degeneration.
- Administered Laquinimod during the cuprizone intoxication period to ameliorate pathology.
- Induced experimental autoimmune encephalomyelitis (EAE) by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide.
- Assessed demyelination, axonal injury, and reactive gliosis via immunohistochemistry.
- Employed Positron Emission Tomography (PET) imaging to analyze in vivo glia activation.
Main Results:
- Vehicle-treated mice showed extensive demyelination, glia activation, and enhanced TSPO-ligand binding.
- Laquinimod treatment significantly ameliorated cuprizone-induced pathology, including demyelination and glia activation.
- In the Cup/EAE model, cuprizone-induced pathology triggered substantial peripheral immune cell recruitment into the brain.
- Laquinimod treatment reduced this secondary immune cell recruitment without altering the primary anti-MOG immune response.
- Neuro-axonal injury and multifocal perivascular inflammation were observed in vehicle-treated Cup/EAE mice.
Conclusions:
- Amelioration of primary brain-intrinsic degenerative processes can halt secondary peripheral immune cell recruitment.
- Targeting neurodegeneration offers a promising therapeutic strategy to prevent inflammatory lesion development in MS.
- These findings have significant implications for interpreting clinical trial results and developing new MS therapies.
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